Enhancing treatment of mdr cancer with adenosine a3 antagonists

Abstract

The present invention discloses the use of high affinity adenosine A 3 receptor antagonists for enhancing chemotherapeutic treatment of cancers expressing adenosine A 3 receptors and cancers expressing P-glycoprotein or MRP. In preferred embodiments, adenosine A 3 receptor antagonists are administered before or during administration of a taxane family, vinca alkaloid, camptothecin or antibiotic chemotherapeutic agent.

1 . A method of countering P-glycoprotein (P-gp) or multidrug resistance-associated protein (MRP) mediated multidrug resistance (MDR) to a drug acting as a substrate for P-gp or MRP by administering to a mammal, in need thereof, a P-gp or MRP inhibiting amount of an adenosine A 3  receptor antagonist of the formula 
     
       
         
         
             
             
         
       
     
     wherein
 A is imidazole, pyrazole, or triazole; 
 R is —C(X)R 1 , —C(X)—N(R 1 ) 2 , —C(X)OR 1 , —C(X)SR 1 , —SO n R 1 , —SO n SR 1  or —SO n —N(R 1 ) 2 ; 
 R 1  is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle or substituted heterocycle wherein each R 1  can be different or the same for any particular compound, or, if linked to a nitrogen atom, then taken together with the nitrogen atom, N(R 1 ) 2  forms an azetidine ring or a 5-6 membered heterocylic ring containing optionally one or more additional heteroatoms selected from N, O, or S; 
 R 2  is hydrogen, alkyl, substituted alkyl, alkenyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl or aryl; 
 R 3  is furan, pyrrole, thiophene, benzofuran, benzopyrrole, benzothiophene, optionally substituted with one or more substituents selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, substituted amino, aminoacyl, acyloxy, acylamino, alkaryl, aryl, substituted aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, thioalkoxy, substituted thioalkoxy, —SO-alkyl, —SO-substituted alkyl, —SO-aryl, —SO-heteroaryl, —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -aryl, —SO 2 -heteroaryl, and trihalomethyl; 
 X is O, S, or NR 1 ; 
 n is 1 or 2; 
 
     or a pharmaceutically acceptable salt thereof. 
   
   
       2 . The method according to  claim 1 , wherein the MDR to a drug is mediated by P-gp. 
   
   
       3 . The method according to  claim 2 , wherein the drug is selected from the group consisting of a taxane family compound, a vinca alkaloid compound, a camptothecin compound and an antibiotic compound. 
   
   
       4 . The method according to  claim 2 , wherein the drug is selected from the group consisting of paclitaxel, docetaxel, vinblastine, irinotecan and doxorubicin. 
   
   
       5 . The method according to  claim 2 , wherein the adenosine A 3  receptor antagonist is a compound of the formula 
     
       
         
         
             
             
         
       
     
     wherein
 A is imidazole, pyrazole, or triazole; 
 R 2  is hydrogen, alkyl, substituted alkyl, alkenyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl or aryl; 
 R 3  is furan; 
 R 6  is aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle or substituted heterocycle; 
 
     or a pharmaceutically acceptable salt thereof. 
   
   
       6 . The method according to  claim 5 , wherein R 2  is selected from the group consisting of hydrogen, alkyl, alkenyl and aryl. 
   
   
       7 . The method according to  claim 6 , wherein A is a triazolo ring. 
   
   
       8 . The method according to  claim 7 , wherein the adenosine A 3  receptor antagonist is selected from the group consisting of MRE3008F20, MRE3046F20, MRE3055F20, MRE3062F20, IL-10 and IL-11. 
   
   
       9 . The method according to  claim 8 , wherein the drug is selected from the group consisting of a taxane family compound, a vinca alkaloid compound, a camptothecin compound and an antibiotic compound. 
   
   
       10 . The method according to  claim 8 , wherein the drug is selected from the group consisting of paclitaxel, docetaxel, vinblastine, irinotecan and doxorubicin. 
   
   
       11 . The method according to  claim 1 , wherein the MDR to a drug is mediated by MRP. 
   
   
       12 . The method according to  claim 11 , wherein the drug is selected from the group consisting of a taxane family compound, a vinca alkaloid compound, a camptothecin compound and an antibiotic compound. 
   
   
       13 . The method according to  claim 11 , wherein the drug is selected from the group consisting of paclitaxel, docetaxel, vinblastine, irinotecan and doxorubicin. 
   
   
       14 . The method according to  claim 11 , wherein the adenosine A 3  receptor antagonist is a compound of the formula 
     
       
         
         
             
             
         
       
     
     wherein
 A is imidazole, pyrazole, or triazole; 
 R 2  is hydrogen, alkyl, substituted alkyl, alkenyl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl or aryl; 
 R 3  is furan; 
 R 6  is aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle or substituted heterocycle; 
 or a pharmaceutically acceptable salt thereof. 
 
   
   
       15 . The method according to  claim 14 , wherein R 2  is selected from the group consisting of hydrogen, alkyl, alkenyl and aryl. 
   
   
       16 . The method according to  claim 15 , wherein A is a triazolo ring. 
   
   
       17 . The method according to  claim 16 , wherein the adenosine A 3  receptor antagonist is selected from the group consisting of MRE3008F20, MRE3046F20, MRE3055F20, MRE3062F20, IL-10 and IL-11. 
   
   
       18 . The method according to  claim 17 , wherein the drug is selected from the group consisting of a taxane family compound, a vinca alkaloid compound, a camptothecin compound and an antibiotic compound. 
   
   
       19 . The method according to  claim 17 , wherein the drug is selected from the group consisting of paclitaxel, docetaxel, vinblastine, irinotecan and doxorubicin.